Acute and chronic kidney injury exacts a profound and growing toll on the health of Americans. The kidney possesses an impressive capacity to repair itself after many forms of acute injury, and a deeper understanding of the cellular and molecular mechanisms of this process will identify new therapeutic approaches to treat human suffereing from kidney failure. Members of the Hedgehog (Hh) family of secreted signaling molecules regulate cell proliferation, differentiation and tissue patterning. They play important roles during nephrogenesis and in other organs are increasingly appreciated as regulators of tissue regeneration. This proposal will investigate the role of hedgehog ligands in kidney homeostasis and repair. Two Hh ligands are expressed in kidney, Indian hedgehog (Ihh) and Sonic hedgehog (Shh), and these are expressed by tubular epithelial cells. Hedgehog responsive cells are located adjacent to epithelia, in the renal interstitium. We hypothesize that crosstalk between Hh-producing epithelia and Hh-responsive interstitial cells maintains cellular differentiation during homeostasis, whereas kidney injury upregulates Hh signaling triggering tissue repair, or if the injury is ongoing, resulting in maladaptive interstitial fibrosis. In Aim 1, we will characterize at the cellular level the expression of Hh pathway components, and examine whether pharmacologic inhibition of Hh signaling during acute injury results in a delay in the re-differentiation of renal epithelia. In Aim 2, we use pharmacologic and genetic gain or loss-of-function approaches to activate or inhibit Hh signaling during acute and chronic renal injury to assess whether modulation of the Hh pathway might represent a novel therapeutic target. In Aim 3, we will specifically address the mechanism by which Hh signals exert their effects in kidney using pericyte cell culture models and we employ in vivo pericyte fate mapping to test whether Hh-responsive cells expand and differente into scar forming myofibroblasts during chronic injury. PUBLIC HEALTH RELEVANCE: The increasing prevalence of chronic kidney disease in our aging population represents an enormous health burden. Because the final common pathway for most chronic nephropathies is renal fibrosis, therapies that reverse or even slow fibrosis would have tremendous clinical impact. These studies will explore the role of a signaling pathway called Hedgehog. Drugs are now being developed to modulate this pathway, so these studies might identify a new use for such drugs in treating kidney fibrosis which remains a tremendous problem in the United States and worldwide.